Abstract C201: Activity of the GlaxoSmithKline kinase inhibitor set on glioblastoma stem cells

Abstract

Abstract Despite significant advances in our understanding glioblastoma (GBM) in recent years, it remains a deadly cancer with a very poor prognosis. There is an urgent need for new therapies. Kinases are well known regulators of cellular growth and survival and there are many compounds available that are capable of inhibiting specific kinases. Recently, GlaxoSmithKline has made available a library of over 350 kinase inhibitors in a public-private partnership to facilitate the discovery of new drugs and targets in multiple disease settings (Nature Chemical Biology 9:3 (2013)). Together these compounds have been shown to inhibit over 100 different kinases by in vitro kinase assay at 1 uM. We have screened these compounds against 3 different GBM stem cell lines under normoxic and hypoxic conditions. Over 40 compounds were strongly inhibitory for least one cell line and condition. However, only 9 of these compounds were capable of inhibiting the growth all three cell lines by 90% at 1 uM in both conditions. Seven of the 9 common inhibitors had IC50's under 100 nM and 4 had IC50's under 10 nM in at least one oxygen condition. In vitro kinase assays indicate that these compounds each have multiple kinase targets. Based on an analysis of common targets, it is likely that one of the targets is PLK1 which is well known GBM inhibitor. Two compounds that don't inhibit PLK1 both inhibit CLK2 and KIT strongly. IC50 analysis demonstrated wide variability among cell lines and oxygen concentrations. The effectiveness of a single compound could vary more then tenfold between cell lines and more than fiftyfold between normoxia and hypoxia. Some compounds were more effective under hypoxia and some were less. These results strengthen the case for personalized therapies and indicate that hypoxia (which is prevalent in GBM) can significantly alter the effectiveness of inhibitors. Citation Format: Simon Khagi, Sejuti Sengupta, Tate Tabtieng, Brent H. Cochran. Activity of the GlaxoSmithKline kinase inhibitor set on glioblastoma stem cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C201.